Substituted 4-propargyloxymethyl-gamma-butyrolactones

ABSTRACT

A COMPOUND OF THE FORMULA   2-(O=),3-(R-CO-),5-(H-C*C-CH2-O-CH2-)-TETRAHYDROFURAN   IN WHICH R IS A STRAIGHT OR BRANCHED-CHAIN ALIPHATIC HYDROCARBON RADICAL HAVING 1 TO 4 CARBON ATOMS, ALKOXY, OPTIONALLY SUBSTITUTED ARYL, -N(-R1)-R2 IN WHICH R1 AND R2 ARE ALIPHATICS HAVING 1 TO 4 CARBON ATOMS, OR A HETEROCYCLIC RADICAL. THE COMPOUND IS PREPARED BY REACTING 1-PROPARGYLOXY-2,3-EPOXY PROPANE WITH NA-CH(-CO-R)-CO-R&#39;&#39; IN WHICH R HAS THE SAME MEANING AS ABOVE AND R&#39;&#39; IS AN ALKOXY. THE COMPOUNDS POSSESS TRANQUILIZING, ANALGESIC AND HYPOTENSIVE PROPERTIES.

United States Patent 3,663,572 SUBSTITUTED 4-PROPARGYLOXYMETHYL- 'y-BUTYROLACTONES Claude P. Fauran, Guy M. Raynaud, and Colette A. Douzon, Paris, and Claude J. Gouret, Meudon, France, assignors to Delalaude S.A., Courbevoie, Hauts-de- Seine, France No Drawing. Filed Aug. 20, 1969, Ser. No. 851,757 Claims priority, application Gr/e6a8t Britain, Sept. 17, 1968,

Int. Cl. C07d /06 US. Cl. 260-3436 5 Claims ABSTRACT OF THE DISCLOSURE A compound of the formula COR in which 'R is a straight or branched-chain aliphatic hydrocarbon radical having 1 to 4 carbon atoms, alkoxy, optionally substituted aryl,

R l .N R2

in which R and R are aliphatics having 1 to 4 carbon atoms, or a heterocyclic radical. The compound is prepared 'by reacting 1-propargyloxy-2,3-epoxy propane with in which R has the same meaning as above and R is an alkoxy. The compounds possess tranquilizing, analgesic and hypotensive properties.

The present invention concerns new substituted 4- proparglyoxymethyl-y-butyrolactones, their process of preparation and their therapeutic application.

The compounds according to the present invention correspond to the following general Formula I:

o HCECCHz-OCHzT To 11 c on (I) with a derivative of the Formula III C O-R Na-G C O-R' (III) in which R has the same significance as in Formula I and R is an alkoxy radical.

3,663,572 Patented May 16, 1972 The following preparations are given as non-limitative examples to illustrate the present invention.

EXAMPLE 1 4-propargyloxymethyl-Z-ethoxycarbonylbutyrolactone 23 g. of sodium are added, with agitation, to 500 cc. of absolute alcohol. After complete formation of the ethylate, 160 g. of ethyl malonate are introduced and the temperature of the mixture is maintained at 55 C. After 30 minutes of contact, 112 g. of 1-propargyloxy-2,3-epoxy propane are progressively introduced and the temperature is maintained, by cooling, between 40 and 50 C. After several hours of contact and returning to normal temperature, the mixture is acidified with 500 ml. of acetic acid and the ethanol is then removed by distillation. The mixture is then taken up in 500 cc. of water and the product formed is extracted with ether. After removal of the solvent, the crude product is obtained which is purified by distillation.

Boiling point=l55-l60 C. under 0.01 mm. Hg Yield1=6l% Elementary analysis.Calculated (percent): C, 58.40; H, 6.24. Found (percent): C, 58.23; H, 6.09;

EXAMPLE 2 4-propargyloxymethyl-2-acetylw-butyrolactone To a solution of sodium ethylate obtained by dissolving 23 g. of sodium in 500 m1. of absolute ethanol, there is added g. of ethyl acetylacetate, and then after one hour of contact at normal temperature, 112 g. of lproparglyoxy-2,3-epoxy propane is added thereto. The temperature is then raised to 50 C. and the mixture is left in contact, with agitation, for several hours. After cooling, the mixture is neutralised with acetic acid and the solvent is removed by distillation. After taking up the residue in water, extracting with ethyl acetate and concentrating the organic phase, the crude product is obtained which is purified by distillation.

Boiling point= C. under 0.1 mm. Hg Yield=65% Elementary analysis.-Calculated (percent): C, 61.21; H, 6.17. Found (percent): C, 61.33; H, 6.41.

EXAMPLE 3 4-propargyloxymethyl-2 [N- dimethyl) carbamoyl] -'ybntyrolactone To a solution of sodium ethylate obtained by dissolving 4.8 g. of sodium in cc. of absolute ethanol, there is successively added 33 g. of ethyl [N-(dimethyl) carbamoyl] acetate and then 23 g. of l-propargyloxy-2,3- epoxy propane. After contact for 3 hours at 25 C. the mixture is cooled and neutralized with acetic acid.

The application of the treatment according to the preceding examples permits the isolation of the desired product by distillation.

Boiling point= C. under 0.1 mm. Hg Yield=20'% The product obtained crystallises in the cold; it is recrystallised from isopropyl ether.

Elementary analysis-Calculated (percent): C, 5 8.65 H, 6.71; N, 6.22. Found (percent): C, 58.73; H, 6.82; N, 6.17.

EXAMPLE 4 4-propargyloxymethyl-Lbenzoyl-y-butyrolactone To a solution of sodium ethylate obtained by dissolving 12.6 g. of sodium in 200 cc. of absolute ethanol,

there is successively added, with agitation, 105 g. of ethyl cologically active dose and the lethal dose is sufiiciently benzoylacetate and then 56 g. of l-propargyloxy-2,3- great to allow the therapeutic utilisation of the compounds epoxy propane. After several hours of contact at ambient of the general Formula 1. temperature, the mixture is neutralised with acetic acid, TABLE II the alcohol is removed and the mixture is treated as in 5 the preceding examples. The oily residue obtained is puriggg? fied by distillation. R g./ g./p.o. percent Boiling point=200-210 C. under 0.02 mm. Hg

. CH3 3.0 50 Yield=41% Elementary analyszs.Calculated (percent): C, 69.75; H, 5.46. Found (percent): 0, 69.91; H, 5.56.

The compounds according to the present invention have CH3 been studied on animals in the laboratory and have been shown to possess tranquilising, analgesic and hypertensive The C mp unds of the general Formula I can be adproperties. ministered for the treatment of anxiety neuroses, pains Tranquilising properties and aches (from any source) and cardiovasculary depressions with hypotension.

They can be used in the form of tablets containing 50 to 400 mg. of active ingredient, ampoules containing doses of 10 to 200 mg. of active ingredient and drops containing 0.5 to 10% of active ingredient.

What we claim is:

The compounds according to the present invention inhibit the mortal convulsions provoked by the administration of pentetrazol in mice.

For example, the DE 50 is 100 mg./kg./P.O. of 4- propargyloxymethyl Z-ethoxycarbonyl-y-butyrolactone.

Analgesic properties 1. A compound of the formula The compounds according to the present invention in- O hibit the painful stretchings provoked by the intra- 2 0 peritoneal injection of acetic acid in mice. H

For example, the protection achieved by 100 mg./kg./ 0 R0. of 4-propargyloxymethyl 2-acetyl- -butyrolactone is C R 45%, in which R is selected from the group consisting of alkyl Hypertensive properties having 1 to 4 carbon atoms, lower alkoxy, phenyl and dimethylamino.

The compounds according to the present invention exercise a progressive and durable hypertensive action on A compound accordlng to clalm m which R is the anaesthetised meghsg. com ound accordin to claim 1 in hi h R 's The results obtained with two of the compounds accordethxy p g W c 1 gg to the present invention are shown in Table I follow- A compound according to claim 1, in which R is 1 phenyl.

TABLE I 5. A compound according to claim 1, in which R is di- Dose Durationof the 40 methylamino' administered, hypertension, References Cited R Wagner and Zoop: Synthetic Organic Chemistry, Wiley CH3 2.5 20 & Sons, N.Y., 1953, p. 534 relied on.

on 2.5 30 a ALEX MAZEL, Primary Examiner '1 A. M. T. TIGHE, Assistant Examiner US. Cl. X.R.

As is shown by the results given above and also in r 4 2 Table II below, the difierence between the pharma- 260 2 6'8424279 

